Effect of sex hormones on HIV infection of cervical and rectal mucosal tissue Sex hormones have a profound effect on the mucosal environment of the female genital tract, however, it is still not clear how they influence vaginal transmission of HIV and if they have an impact on the rectal microenvironment and rectal transmission. The data demonstrating increased HIV acquisition in women using hormonal contraception, primarily Depo-Provera, suggest that high progestin level may lead to enhanced HIV transmission. In fact, patients on oral hormonal contraceptives or Depo-Provera have an increased number of activated CCR5+ T cells in the genital mucosa. Further supporting this idea are data in non-human primates demonstrating increased vaginal SIV transmission in Depo-Provera treated animals and in animals during luteal phase of the menstrual cycle which is characterized by high progesterone levels. Recent data demonstrate that anal intercourse is more prevalent among women than previously thought, and therefore can impact interpretation of data on effect of sex hormones during heterosexual HIV transmission. While the evidence for a role of hormones in HIV vaginal transmission is compelling, it is likely that sex hormones influence the rectal mucosal microenvironment as well. In fact, sex hormones are involved in regulation of inflammation in the gut tissue. Therefore, it is important to establish their role in rectal HIV transmission, as well as vaginal transmission. We hypothesize that increased progestins/progesterone levels are associated with increased susceptibility of ecto-, endocervical and rectosigmoid mucosa to HIV due to (i) changes in HIV target cell numbers and phenotype, (ii) suppression of baseline innate immune factors that limit HIV infection, (iii) suppression of virus-induced responses that protect against infection in the mucosa. We will explore this by determining if the susceptibility of cervical vs. rectosigmoid tissues to in vitro IV infection correlates with systemic progestin/progesterone levels (exogenous vs. endogenous) in women and whether this also parallels changes in tissue immune function. These studies will determine if there is a link between progestins/progesterone levels (systemic, tissue) and HIV infection in both the cervical and rectosigmoid tissues. Furthermore, we will address the mechanism of progestin/progesterone action at both sites by focusing on the immune environment and potentially identify underlying factors that influence a woman's susceptibility to HIV infection.